Eighteen years after identification of the CFTR gene we still lack answers to many crucial questions. Controversies surround the pathogenesis of airway disease, current treatments are inadequate, and cystic fibrosis (CF) remains a lethal disease. A major impediment to progress has been lack of a CF animal model other than the mouse. CF mice fail to develop lung disease, the cause of most CF morbidity and mortality. Therefore, we disrupted the CFTR gene in the pig, whose lungs resemble those of humans. In this Program four senior and highly accomplished investigators will seize the unique opportunity to use CFTR -I- pigs to answer key questions about CF lung disease. Together, the four projects will discover how loss of CFTR causes airway epithelial and submucosal gland dysfunction and how that contributes to airway inflammation and infection. The Project Leaders have an outstanding track record of collaboration in CF, and here they sharpen their focus to a common goal. Their research is highly creative and is supported by five cores that provide innovative services and infrastructure. Discoveries from this PPG will accelerate development of novel therapies for patients who suffer from this devastating disease.